Fluorinated organic molecules are increasingly used in life science industries. The presence of a fluorine substituent can have positive effects on the biological properties of compounds. Thus, synthetic techniques for fluorinating compounds are a significant area of interest.
The selective fluorination of aryl and heteroaryl substrates is a challenging synthetic problem. As an example, mono- and di-chloro substituted picolinate esters are difficult to fluorinate and require more expensive metal fluorides (e.g., cesium fluoride (CsF)) to generate acceptable yields. Under Halex (halogen exchange) conditions, which use potassium fluoride, the chemical yields are often quite low (<20%). Also, Halex conditions usually require a phase transfer catalyst, a high boiling solvent, and high temperatures. Such conditions can preclude the use of Halex conditions in many systems.
Tetrabutylammonium fluoride (TBAF) has been used as a highly nucleophilic fluoride-ion source to fluorinate a variety of substrates. This reagent is prepared by treating tetrabutylammonium cyanide with hexafluorobenzene in a solvent and under anhydrous conditions. The resultant TBAF (i.e., TBAFanh or TBAF*) can then be used to fluorinate certain substrates. See DiMagno et al. J. Am. Chem. Soc. 2005, 127, 2050-2051; DiMagno et al. Angew. Chem. Int. Ed. 2006, 45, 2720-2725.
While TBAF* has been successful in certain systems, it has limitations, such as poor selectivity and reactivity for difficult substrates like chloropyridines, especially those of the 6-arylpicolinate family. Other limitations include the necessity for pre-formation of TBAF* for every batch of reactions and fluorinations demonstrated in only DMSO. What are needed are new methods for fluorinating compounds and the methods and compounds disclosed herein address these and other needs.